An increasing number of microbial strains have acquired resistance to the currently available antibiotic compounds, resulting in a potentially dangerous threat to public health. Thus the need for expanding the options available to treat microbial-based conditions has grown with the increasing use of antibiotics. The need for new antimicrobial compounds extends beyond treatment of human and animal infections to a need to preserve food and other perishable commodities. New antibiotics can also be essential for treatment of plants having microbial infections and to the preservation of materials that otherwise are subject to microbially caused corrosion. Thus, there is a clear need for an expanded armament of compounds which can provide a multifaceted defense against unwanted microbial activity.
U.S. Pat. No. 5,866,549 (which is incorporated herein by reference) and U.S. Pat. No. 5,635,485 disclose modified forms of erythromycin which lack a cladinose residue at the 3-position and which are derivatized in various ways in positions 9-12 of the macrolide ring. Such erythromycin derivatives lacking the cladinose and having a 3-keto group are termed “ketolides.” U.S. Pat. No. 5,750,510 (incorporated herein by reference) also discloses modified erythromycin derivatives. All of the compounds disclosed in the above-referenced patent documents are derived from erythromycin A, and thus contain an ethyl group at position 13 of the macrolide ring.
While erythromycin A and its chemical derivatives have found long-standing use in the treatment of microbial diseases, it has recently been discovered that these antibacterials have significant safety risks associated with their use. In particular, these antibacterials have been shown to inhibit certain ion channels in cardiac tissues resulting in lengthening of the QT interval in the electrocardiogram. Such lengthening of the QT interval is associated with induction of torsades de pointes in susceptible individuals, occasionally leading to cardiac arrest. See, for example, H. Ohtani et al., “Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats,” Antimicrobial Agents & Chemotherapy (2000) 44: 2630-2637. The principal cardiac ion channel thought to be involved in this, the hERG or IrK channel, is inhibited by a wide range of drugs with no clear structure-activity relationship, precluding prediction of intrinsic binding affinities of drugs to the channel. Further, hERG is a membrane-spanning ion channel with extracellular and cytosolic faces, and inhibition of hERG by erythromycin-like antibacterials is believed to occur by binding of the drug to the cytosolic face of the channel. As erythromycin-like antibiotics are often actively accumulated into cells at unpredictable levels, the effects of particular macrolide antibacterials on the QT interval are extremely complex and impossible to predict based on their structure.
There thus exists a need for new antibacterial agents having improved efficacy and cardiac safety. U.S. Pat. No. 6,395,710 (incorporated herein by reference) discloses ketolide antiinfective agents prepared from analogs of erythromycin A, which are in turn prepared by genetic engineering. These ketolides show improved activity against a range of erythromycin-sensitive and resistant microorganisms. After extensive testing, we have unexpectedly discovered particular combinations of substituents on these compounds that provide not only improved antibacterial activity but also improved pharmacokinetic behavior and cardiac safety. Such compounds are of particular importance for the safe, effective treatment of bacterial infections.